Coronary heart disease (CHD) is a leading cause of death in the United States. Annual costs of approximately S475 billion have been estimated by the NIH for heart and stroke diseases. Myocardial perfusion scintigraphy is widely employed in the evaluation of patients with known or suspected coronary artery disease (CAD) and myocardial perfusion imaging (MPI) has acquired great value in nuclear cardiology. While 99mTc-Sestamibi and 201Tl, both single photon agents, have dominated the MPI field for the past two decades, there has been great interest in the development of Positron Emission Tomography (PET) perfusion agents to exploit the potential for enhanced spatial and dynamic resolution that PET offers. However, no 18F-based agent is yet clinically available. Interestingly, there has been a recent increase in world-wide intensity for developing 68Ga-based radiopharmaceuticals as potential new PET agents, which may provide a non-cyclotron-based resource for new PET radiopharmaceuticals and applications. In addition, recent threats to the stable production and supply chain of 99mTc have added further urgency to the search for a viable PET perfusion agent. Among the several agents that are commercially available for perfusion imaging, all of these suffer from one or more shortcomings that render them less than ideal for cardiac perfusion studies. Among these shortcomings are: a) limited first pass extraction at high flow (99mTc-Sestamibi and Thallous Chloride Tl-201) and b) poor liver clearance (99m-Sestamibi, 99mTc-teboroxime. 99mTc-Tetrofosmin, and 99mTc-Q complexes). While the former factor can decrease sensitivity, the latter component can increase background noise from adjacent tissues thereby atficting signal-to-noise ratios. The resulting image quality can be less than optimal for interpretation by clinicians in nuclear medicine or physicians such as radiologists.
Positron Emission Tomography (PET) technology allows a three dimensional reconstruction of the distribution of radiopharmaceuticals in vivo to quantify tissue activity levels and allow high resolution imaging. Ga-68 is considered a short-lived positron emitting radionuclide available from 68Ge/68Ga generator systems. These systems are widely available in Europe and are employed for clinical applications across the continent. Such generator systems can be installed in any small nuclear medicine facility nationwide and are not dependent on cyclotrons to produce PET radionuclides. Furthermore, there are two gallium radioisotopes: Ga-68 and Ga-67. The other radionuclide, Gallium-67 can be produced from a cyclotron from Zinc-68 and has a half-life of 78.2 hours, and is commercially available as radioactive gallium chloride or gallium citrate for single photon emission computed tomography (SPECT) applications.
The multidrug resistance (MDR1) P-glycoprotein (Pgp; ABCB1) is an outwardly directed membrane transporter expressed on the cell surface of many normal tissues as well as multidrug resistance cancers. Because Pgp is also expressed on the biliary surface of hepatocytes, the transporter functions to excrete substances into the bile. Thus, MPI agents that are recognized by Pgp, such as 99mTc-sestambi, show rapid clearance profiles from the liver, which significantly reduces cross-contamination of liver signals into the inferior wall of the myocardium. This important property results in more reliable and enhanced quantitative analysis of myocardial images in nuclear medicine clinics.
Pgp is also localized on the luminal surface of vascular endothelial cells of the brain and serves as a component of the blood-brain barrier (BBB). Acting as an efflux transporter, Pgp is believed to block brain uptake of moderately hydrophobic drugs by directly excluding such substances from the CNS compartment, thereby offering a natural protection mechanism for the brain. Apart from the well-characterized role of Pgp as a mediator of chemotherapeutic multidrug resistance in cancer patients, Pgp has also been postulated to play an important role in development of Aβ-pathophysiology within the brain, as well as in other neurodegenerative disorders. Additionally, many agents recognized by Pgp are moderately hydrophobic as well as cationic under physiological conditions; some hydrophobic cations are known to penetrate Pgp negative cells or tissues in response to negative transmembrane potentials (both plasma- and mitochondrial potentials), and are localized within the mitochondria. Among various tissues, myocardium is mitochondrial rich and is also a Pgp negative tissue.
WO2008/128058 of H. Kung discloses a compound of formula
or a pharmaceutically acceptable salt thereof, wherein A1, A2 and A3 are the same or different cycloalkyl, wherein at least one of A1, A2 or A3 is substituted; R1, R2, R3, R4, R5, and R6 are independently hydrogen or alkyl; R7 and R8 are independently hydrogen or alkyl, and RP is hydrogen or a sulthydryl protecting group.